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The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells

Lookup NU author(s): Dr Arianna Montanari, Dr Helen Tuppen, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0).


Mitochondrial (mt) diseases are multisystem disorders due to mutations in nuclear or mtDNA genes. Among the latter, more than 50% are located in transfer RNA (tRNA) genes and are responsible for a wide range of syndromes, for which no effective treatment is available at present. We show that three human mt aminoacyl-tRNA syntethases, namely leucyl-, valyl-, and isoleucyl-tRNA synthetase are able to improve both viability and bioenergetic proficiency of human transmitochondrial cybrid cells carrying pathogenic mutations in the mt-tRNA(Ile) gene. Importantly, we further demonstrate that the carboxy-terminal domain of human mt leucyl-tRNA synthetase is both necessary and sufficient to improve the pathologic phenotype associated either with these mild mutations or with the severe m.3243A>G mutation in the mt-tRNA(Leu(UUR)) gene. Furthermore, we provide evidence that this small, non-catalytic domain is able to directly and specifically interact in vitro with human mt-tRNA(Leu(UUR)) with high affinity and stability and, with lower affinity, with mt-tRNA(Ile). Taken together, our results sustain the hypothesis that the carboxy-terminal domain of human mt leucyl-tRNA synthetase can be used to correct mt dysfunctions caused by mt-tRNA mutations.

Publication metadata

Author(s): Perli E, Giordano C, Pisano A, Montanari A, Campese AF, Reyes A, Ghezzi D, Nasca A, Tuppen HA, Orlandi M, Di Micco P, Poser E, Taylor RW, Colotti G, Francisci S, Morea V, Frontali L, Zeviani M, d'Amati G

Publication type: Article

Publication status: Published

Journal: EMBO Molecular Medicine

Year: 2014

Volume: 6

Issue: 2

Pages: 169-182

Print publication date: 01/02/2014

Online publication date: 10/01/2014

Acceptance date: 17/10/2013

Date deposited: 15/08/2014

ISSN (print): 1757-4676

ISSN (electronic): 1757-4684

Publisher: Wiley-Blackwell Publishing


DOI: 10.1002/emmm.201303198


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Funder referenceFunder name
Associazione Talarico per i giovani nel mondo
Istituto Pasteur-Fondazione Cenci Bolognetti
Pasteur Institute-Cenci Bolognetti Foundation
Sapienza, University of Rome
096919/Z/11/ZWellcome Trust